Abstract
BackgroundFacioscapulohumeral dystrophy (FSHD) is a progressive muscle disease caused by mutations that lead to epigenetic derepression and inappropriate transcription of the double homeobox 4 (DUX4) gene in skeletal muscle. Drugs that enhance the repression of DUX4 and prevent its expression in skeletal muscle cells therefore represent candidate therapies for FSHD.MethodsWe screened an aggregated chemical library enriched for compounds with epigenetic activities and the Pharmakon 1600 library composed of compounds that have reached clinical testing to identify molecules that decrease DUX4 expression as monitored by the levels of DUX4 target genes in FSHD patient-derived skeletal muscle cell cultures.ResultsOur screens identified several classes of molecules that include inhibitors of the bromodomain and extra-terminal (BET) family of proteins and agonists of the beta-2 adrenergic receptor. Further studies showed that compounds from these two classes suppress the expression of DUX4 messenger RNA (mRNA) by blocking the activity of bromodomain-containing protein 4 (BRD4) or by increasing cyclic adenosine monophosphate (cAMP) levels, respectively.ConclusionsThese data uncover pathways involved in the regulation of DUX4 expression in somatic cells, provide potential candidate classes of compounds for FSHD therapeutic development, and create an important opportunity for mechanistic studies that may uncover additional therapeutic targets.
Highlights
Facioscapulohumeral dystrophy (FSHD) is a progressive muscle disease caused by mutations that lead to epigenetic derepression and inappropriate transcription of the double homeobox 4 (DUX4) gene in skeletal muscle
Genes regulated by DUX4, most of which are undetectable in normal muscle but readily measurable in FSHD myoblasts and myotubes, provide abundant and stable RNAs that are sensitive and highly specific markers of DUX4 expression [13, 27]
We carried out two such screens, differing primarily in the content of the compound libraries with minor distinctions in outcome measures, using FSHD muscle cells differentiated in culture to identify molecules that decrease DUX4 target gene induction
Summary
Facioscapulohumeral dystrophy (FSHD) is a progressive muscle disease caused by mutations that lead to epigenetic derepression and inappropriate transcription of the double homeobox 4 (DUX4) gene in skeletal muscle. FSHD is caused by the mis-expression of the double homeobox 4 (DUX4) transcription factor in skeletal muscle. DUX4 mis-expression in skeletal muscle induces early embryo, stem cell, and germline genes; activates repetitive elements; suppresses innate immune response and nonsense-mediated RNA decay pathways; inhibits myogenesis; and causes cell death through mechanisms that include the accumulation of aberrant and double-stranded RNAs [13,14,15,16,17,18,19,20,21,22]
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